Effects of consanguinity in a cohort of subjects with certain genetic disorders in Qatar.

BACKGROUND: Consanguineous marriages are common in the Middle East including the Gulf countries. The rate of consanguinity in Qatar is approximately 54%, which are mainly first cousins' marriages. Previous studies showed that consanguinity increases the prevalence of birth defects and other genetic disorders. Thus, we studied the effects of consanguinity in a cohort of subjects with certain genetic disorders in Qatar. METHODS: This cross-sectional study was conducted at two centers in Qatar (Hamad Medical Corporation "HMC" and Shafallah "SC") including 599 Qatari families with certain types of genetic and nongenetic anomalies. RESULTS: Consanguineous marriages were seen in 397 of 599 (66.2%) Qatari families and first cousin group counts for 65% in Qatari population. In the total cohort and at HMC, all consanguineous marriages had a significantly higher risk of Autosomal Recessive disorders than nonconsanguineous marriages (total cohort: odds ratio (OR) = 1.72; 95% CI: 1.10, 2.71; p = .02; HMC: OR = 2.98; 95% CI: 1.37, 6.09; p = .005). On the other hand, at HMC, nonconsanguinity was significantly related to chromosomal abnormality (OR = 6.36; 95% CI: 1.13, 35.85; p = .036). CONCLUSION: Our data suggest a significant role of parental consanguinity in increasing the prevalence of genetic disorders; mainly Autosomal Recessive disorders. Chromosomal abnormality disorders were significantly higher among nonconsanguineous marriages. These results help better inform policy makers on social, educational, and public health initiatives that might mitigate the impact of genetic disease in the Qatari society.

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

Extraction of airways from CT (EXACT'09).

This paper describes a framework for establishing a reference airway tree segmentation, which was used to quantitatively evaluate fifteen different airway tree extraction algorithms in a standardized manner. Because of the sheer difficulty involved in manually constructing a complete reference standard from scratch, we propose to construct the reference using results from all algorithms that are to be evaluated. We start by subdividing each segmented airway tree into its individual branch segments. Each branch segment is then visually scored by trained observers to determine whether or not it is a correctly segmented part of the airway tree. Finally, the reference airway trees are constructed by taking the union of all correctly extracted branch segments. Fifteen airway tree extraction algorithms from different research groups are evaluated on a diverse set of twenty chest computed tomography (CT) scans of subjects ranging from healthy volunteers to patients with severe pathologies, scanned at different sites, with different CT scanner brands, models, and scanning protocols. Three performance measures covering different aspects of segmentation quality were computed for all participating algorithms. Results from the evaluation showed that no single algorithm could extract more than an average of 74% of the total length of all branches in the reference standard, indicating substantial differences between the algorithms. A fusion scheme that obtained superior results is presented, demonstrating that there is complementary information provided by the different algorithms and there is still room for further improvements in airway segmentation algorithms.